This 5 year-proposal describes a comprehensive plan for the development of a career in experimental pathology. The principal investigator completed anatomic pathology residency and hematopathology fellowship training at Stanford University and has spent the past two years honing his skills as a diagnostic hematopathologist while spending the majority of his time developing the technical and intellectual skills that will allow him to become an independent investigator. The proposed work will take place in the laboratory of Irving L. Weissman, an internationally recognized leader in the field of stem cell biology, cancer stem cell biology, and hematopoiesis. Given the breadth and depth of intellectual and technological resources, Dr. Weissman's lab represents a unique environment, geared not only to allowing highly creative and innovative projects to come to fruition, but also to train future independent investigators. Given the growing evidence that microRNAs play a role in the development of human cancers, this proposal represents a timely investigation into the pathogenesis of human acute myeloid leukemia (AML). Unlike conventional cancer biology research, the proposed studies will focus on the tumor-initiating, or stem cells, of AML. Because of the unique properties of leukemia stem cells (LSC), including the capacity to initiate tumors, self-renew, and recapitulate disease in xenograft models, it is imperative that we understand the molecular basis of the AML LSC biologic properties. Because of the unique experimental challenges associated with working with primary human samples, a great deal of time has been, and will continue to be, invested in developing improved models to study the role of microRNAs in human AML. The Stanford Institute for Stem Cell Biology and Regenerative Medicine is an ideal setting for these studies. In addition to housing a community of cancer and stem cell biologists, there are numerous opportunities to collaborate with members of other departments through interdisciplinary programs including the Stanford Comprehensive Cancer Center, Immunology Program, and many others. Given the strength of Stanford's clinical divisions (adult and pediatric hematology/oncology, bone marrow transplant, hematopathology), there is significant tissue access as well as opportunities to work with clinical colleagues.